Hereditary breast cancer (HBC) is considered to be a heterogeneous disorder with genetic transmission by an autosomal dominantly inherited, highly penetrant, cancer susceptibility gene(s). A large number of kindreds segregating this trait are currently under study by us. Recent advances in genetics, including improvements in the human genetic linkage map, and findings of linkage in several cancer susceptibility disorders, make linkage studies of HBC families possible and urgent. We propose a multicentered collaboration using extensive blood sample collection in a small but carefully selected set of highly informative HBC families (500 individuals in 8 families) to enable the most sophisticated molecular genetic and statistical methods, currently available, to be applied to the search for linkage. In tandem with blood collection for linkage studies, we will collect tumor specimens (slides and paraffin-embedded tumor blocks) from approximately 200 breast cancer-affected members of HBC and nonHBC. We will use the specimens to extend our pilot studies contrasting HBC and nonHBC breast cancers as clinicopathologically distinct subsets, with emphasis on tumor histology, mitotic grade, ploidy, and proliferation measured by flow cytometry. We will also create and maintain an archive of tumor specimens for future tumor marker studies which are not part of the present proposal but which will be targeted by findings in the linkage study. This effort harbors the potential for identifying the HBC gene(s) and extending knowledge of HBC's pathology so that knowledge of HBS's etiology and pathogenesis might be further elucidated. This achievement would have profound control implications.